Correlations between genetic polymorphism of IFN-λ family gene and HBV infection, virus replication and clearance / 生物工程学报

Hepatitis B virus (HBV) infection is one of the most serious public health problems. HBV infection could lead to hepatitis B, and even further develop into hepatic cirrhosis and hepatocellular carcinoma. Interferon lambda (IFN-λ) is a member of the interferon (IFN) family and an important cytokine for antiviral defense. There are four members in IFN-λ family, including IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4. The genetic polymorphisms in the IFN-λ genes are associated with HBV replication and treatment response of HBV patients. In this review, we summarized the roles of genetic polymorphisms of the IFN-λ genes played in HBV infection, disease progression and treatment, with the aim to better understand their function. This review could serve as a reference for the HBV prevention and treatment of HBV patients, as well as for future clinical usage.

La evidencia en tiempos de coronavirus (COVID-19) / Evidence in times of coronavirus (COVID-19)

La pandemia de COVID-19 está generando información epidemiológica y clínica en una escala sin precedentes para una enfermedad de reciente aparición. Aunque ya se han iniciado numerosos ensayos clínicos de fármacos antiguos y nuevos como potenciales antivirales específicos, la mayor parte de la información publicada hasta ahora carece de los controles básicos para la evaluación de la eficacia de un medicamento. Los medios de comunicación amplifican estos resultados preliminares y suman presión a los médicos asistenciales y a los decisores de políticas públicas. Este artículo revisa las pruebas disponibles sobre los cuatro tratamientos antivirales específicos más prometedores: hidroxicloroquina, lopinavir/ritonavir, remdesvir e interferones alfa y beta. Se comprueba en todos ellos que no hay demostración suficiente de eficacia como para recomendar su uso fuera de una investigación experimental adecuadamente controlada. En el uso individual de un medicamento no hay forma de saber si está beneficiando o perjudicando al paciente. Es erróneo asumir que la eventual curación se debe al fármaco y un mal desenlace debe atribuirse a la enfermedad. Sólo la comparación entre grupos de pacientes asignados al tratamiento experimental o a un control adecuado permite conocer la eficacia y seguridad de las intervenciones. El desafío es conciliar la urgencia de actuar con la generación de nuevos conocimientos.Aunque no resulta sencillo organizar ensayos clínicos en este contexto, las instituciones pueden sumarse a los proyectos en marcha a nivel nacional e internacional. El uso de estos fármacos debe considerarse experimental, por lo que es necesario obtener el consentimiento informado del paciente. (AU)

The COVID-19 pandemic is generating epidemiological and clinical information on an unprecedented scale for a newly emerging disease. Although numerous clinical trials of old and new drugs as potential specific antivirals have already been started, most of the information published so far lacks basic controls for evaluating drug efficacy. The media amplify these preliminary results and add pressure to doctors and policymakers. This article reviews the available evidence for the four most promising specific antiviral treatments: hydroxychloroquine, lopinavir / ritonavir, remdesvir, and alpha and beta interferons. The findings show that none of them has sufficient demonstration of efficacy to recommend its use outside ofthe adequately controlled experimental study. In the individual use of a drug there is no way of knowing if it is benefiting orharming the patient. It is wrong to assume that the eventual cure is due to the drug and a poor outcome must be attributed to the disease. Only the comparison between groups of patients assigned to the experimental treatment or to an adequate control can establish the efficacy and safety of the interventions. The challenge is to reconcile the urgency to act with the generation of new knowledge. Although it is not easy to organize clinical trials in this context, the institutions can join theongoing projects at the national and international levels. The use of these drugs should be considered experimental, so it is necessary to obtain the informed consent of the patient. (AU)

Avaliação da presença de mutações de resistência no gene da NS5B e do prognóstico da infecção pelo HCV através da IL-28B em pacientes monoinfectados com HCV no RJ / Evaluation of resistance mutations presence in the NS5B gene and prognosis of HCV infection throught IL-28B in HCV monoinfected patients of RJ

Estima-se que a prevalência global da população mundial com hepatite C é de 3%. Pouco se sabe sobre a resposta ao tratamento com respeito à resistência viral. Algumas mutações no fragmento de 109 aminoácidos da NS5B são associadas com resistência ao interferon (IFN) e ribavirina (RBV). Estudos moleculares e clínicos identificaram fatores associados com o hospedeiro e vírus relacionados associada com a resposta ao tratamento, tal como o gene que codifica a IL-28B. Este estudo foi dividido em duas fases, cujos objetivos foram caracterizar a frequência de mutações que conferem resistência ao HCV e avaliar a relevância das mutações em pacientes Respondedores (R) ou Não Respondedores (NR) ao tratamento e caracterizar geneticamente as populações sobre polimorfismos genéticos nos SNPs da IL-28B em relação ao prognóstico da resposta ao tratamento. As amostras dos pacientes foram submetidas a testes de genotipagem e carga viral. As sequências geradas foram comparadas no BLAST e no banco de dados Los Alamos HCV. Realizamos o alinhamento das sequências homólogas e as mutações identificadas. Com base no genótipo e carga viral determinamos a classificação dos pacientes de acordo com a resposta à terapia. O DNA genômico foi isolado a partir de sangue periférico para a realização da tipagem de SNPs de IL-28B. A metodologia utilizada foi de PCR em tempo real utilizando sondas TaqMan SNP específico. A análise dos dados foi realizada utilizando GraphPad Prism com qui-quadrado, risco relativo (RR), Odds Ratio (OR) e intervalo de confiança de 95%, com um nível de significância de P <0,05. Foi encontrado na primeira fase deste estudo uma taxa significativa mutações associadas ao tratamento nas amostras estudadas. A prevalência de mutações associadas à resistência ao IFN e RBV bem como a novos medicamentos antivirais localizados no fragmento de 109 aminoácidos da NS5B foi examinado em 69 indivíduos infectados naïve no Rio de Janeiro, Brasil. Na segunda fase, as mutações foram ...

It is estimated that the overall prevalence of the average world population with hepatitis C is 3%. Little is known about the treatment response with respect to viral resistance. Some mutations in the 109-aminoacid fragment of NS5B are associated to Interferon (IFN) and Ribavirin (RBV) resistance. Molecular and clinical studies have identified factors associated with the host and related viruses associated with response to treatment, as the gene encoding IL-28B. This study was divided into two phases whose objectives were to characterize the frequency of mutations conferring resistance to HCV viral evaluating the relevance of these in Responders (R) or Non-Responders (NR) patients to treatment and to characterize genetically the populations regarding genetic polymorphisms SNPs IL-28B in relation to prognosis of response to treatment for HCV. Patient samples were subjected to tests for genotyping and viral load. The sequences generated were compared in the BLAST and the Los Alamos database HCV. We conducted the alignment of homologous sequences and mutations identified. Based on virological parameters genotype and viral load determined the classification of patients according to response to therapy. Genomic DNA was isolated from peripheral blood for carrying out the typing of SNPs of IL-28B. The methodology used was real-time PCR using TaqMan probes specific SNPs. Data analysis was performed using GraphPad Prism with chi-square, relative risk (RR), Odds Ratio (OR) and confidence interval of 95% with a significance level of P <0.05. To study these biological parameters we associated the responsive patients, non-responders, the viral load, genotype, and IL-28B polymorphism to treatment outcome. We found in the first phase of this study a significant rate of treatment-associated mutations in the samples studied. The prevalence of mutations associated to resistance to interferon and ribavirin (IFN/RBV) as well new antiviral drugs located in the 109 aminoacid ...

Association of hepatitis C virus NS5B variants with resistance to new antiviral drugs among untreated patients

Mutations located in the 109-amino acid fragment of NS5B are typically associated with resistance to interferon (IFN) and ribavirin (RIB) and to new antiviral drugs. The prevalence of these mutations was examined in 69 drug-naïve individuals with hepatitis C virus (HCV) infections in Rio de Janeiro, Brazil. Mutations related to non-response to IFN/RIB were observed in all subtypes studied (1a, 1b, 2b, 3a and 4). The most common mutation was Q309R, present in all subtypes, except subtype 2b with frequency above 20 percent. D244N was detected only in subtype 3a and A333E was detected only in subtype 2b. We did not detect the S282T, S326G or T329I mutations in any of the samples analysed. Of note, the C316N mutation, previously related to a new non-nucleoside compound (HCV796 and AG-021541), was observed in only eight of 33 (24 percent) samples from subtype 1b. Site 316 was under positive selection in this HCV variant. Our data highlight the presence of previously described resistance mutations in HCV genotypes from drug-naïve patients.

Papel da proteína Mx1 na resposta a interferons e no processo neoplásico / Role of Mx1 protein in the response to interferons and neoplastic process

A proteína Mx1 é codificada por um gene induzido por interferon e compartilha a organização de seus domínios, a capacidade de homo-oligomerização e associação com membranas com as grandes dinaminas GTPases. A proteína Mx1 está envolvida na resposta contra um grande número de vírus de RNA, como aqueles pertencentes à família Buniavírus e o vírus influenza. Curiosamente, o gene MX1 foi encontrado como silenciado por metilação em diversos processos neoplásicos, incluindo carcinomas de cabeça e pescoço de células escamosas. Neste cenário, o silenciamento gênico de MX1 está associado à imortalização de uma série de linhagens celulares neoplásicas. Assim, Mx1 se destaca como uma das principais proteínas envolvidas nas respostas imunes induzidas por interferon e também desempenha um importante papel no controle do ciclo celular. Aqui discutimos os aspectos funcionais da proteína Mx1 abordando sua atividade antiviral, organização estrutural, envolvimento com neoplasias e, principalmente, os aspectos funcionais obtidos pela determinação de seus parceiros celulares.

The Mx1 protein is encoded by an interferon-induced gene and shares domain organization, homo-oligomerization capacity and membrane association with the large dynamin-like GTPases. The Mx1 protein is involved in the response to a large number of RNA viruses, such as the bunyavirus family and the influenza virus. Interestingly, it has also been found as a methylation-silenced gene in several types of neoplasm, including head and neck squamous cell carcinoma. In this scenario, MX1 gene silencing is associated with immortalization in several neoplastic cell lines. Thus, Mx1 stands out as one of the key proteins involved in interferon-induced immune response and also plays an important role in cell cycle control. Here we discuss some of the functions of the Mx1 protein, including its antiviral activity, protein folding and involvement in neoplasia, as well as those revealed by investigating its cellular partners.

The use of interferons in the treatment of pre-invasive cervical neoplasias

The evolution of cervical intraepithelial neoplasias(CINs) can lead to the development of cervical carcinomas and is closely tied to infection with human papillomavirus (HPV). Interferon (IFN)’s antitumor effects have a direct bearing on the proliferation or antigen composition of tumor cells, and act on specific tumor cells through immunomodulation. Moreover, some studies have indicated that type 1 IFN can have an antitumor effect by increasing levels of cytotoxic T cells,natural killer (NK) cells and dendritic cells (DCs). Immunotherapy with IFN has recently been used on cervical intraepithelial lesions and invasive cervical cancer with promising results. The objective of this mini-review isto discuss IFNs’ function, importance, and mechanism of action in the treatment of pre-malignant cervicalneoplasias.

Interferón: 50 años después (1957-2007) / A review of interferons: fifty years later (1957-2007)

Identificados inicialmente como un mecanismo de defensa contra las infecciones virales, en el transcurso de los últimos 50 años se ha definido que los interferones forman parte de la extensa familia de las citocinas, sustancias indispensables para el funcionamiento del sistema inmunológico. Debido a sus diversas funciones pleiotrópicas, los interferones fueron las primeras citocinas empleadas para el manejo de una amplia gama de padecimientos, propiedades que progresivamente los han colocado como medicamentos de primera elección para el tratamiento de la infección crónica por el virus de la hepatitis B, virus de la hepatitis C, esclerosis múltiple, algunas leucemias, melanoma, etc. No obstante, la administración de dosis suprafisiológicas de interferones con fines terapéuticos, independientemente de su indicación primaria, se han asociado con toxicidad importante, incluyendo la inducción de autoinmunidad y más de 30 enfermedades autoinmunes diferentes.

Initially identified as a defense mechanism against viral infections, in the last 50 years interferons have been defined a group of substances belonging to the cytokine family indispensable for the normal functioning of the immune system. Derived from their pleiotropic functions interferons were the first biological products used to treat several diseases. Their properties have progressively placed them as the first treatment choice for chronic infection with hepatitis B virus, hepatitis C virus, multiple sclerosis, some forms of leukemia, melanoma, etc. It has been noted however that the administration of supra physiological doses of interferons with therapeutic objectives, independently of its primary indication, has been associated with significant toxicity, including autoimmunity and induction of more than thirty different autoimmune diseases.

Cloning and analysis of IFRG (interferon responsive gene) in rabbit oocytes and preimplantation embryos

Although there is more evidence that shows that IFNs (interferons) plays a very important role in the early development of the embryo, the mechanism of IFNs is still unclear. Our study showed that IFRG is expressed from oocytes- through to the preimplantation embryo in rabbits. This finding provides some clues for better understanding the role of IFNs in the development of the embryo. The full length of rabbit IFRG cDNA (Accession No. AJ584672), with a 2794bp encoding 131 amino acid sequence, was cloned IFRG expression can be detected in 8 different tissues: ovary, heart, lung, liver, kidney, spleen, cerebra, and the 18-day whole-body embryo. Whole-mount in situ hybridization showed that IFRG was highly expressed in the inner-cell mass of rabbit blastula. IFRG may play an important role in embryo development and tissue differentiation.

Hepatitis C virus genotypes: special reference to the Indian scene.

The heterogeneity observed between different isolates of the hepatitis C virus has led to stratification of these isolates into different genotypes. Clinically the genetic diversity of the virus has important implications as genotypes respond variably to antiviral therapy and can influence disease prognosis. This article attempts to summarize current knowledge about the different biological properties of HCV genotypes, and their geographical distribution, with special reference to the Indian scenario.

Citocina. ¿La terapéutica del futuro? / Citokines. The therapy in the future?

Se definen qué son las citocinas y se describe el papel de la interleucina-1 como un ejemplo de las fuciones que desempeñan. Actualmente se han encontrado más de 40 citocinas que se han agrupado en 1) factores de crecimiento, 2) interleucinas, 3) interferones, 4) quimiocinas y 5) otras. Hoy en día, mediante transfección genética, se han preparado 11 citocinas para aplicación terapéutica; de éstas, la eritropoyetina, el factor estimulante de colonias granulocito-monocito y el factor estimulante de colonias granulocito-monocito y el factor estimulante de colonias de granulocitos se utilizan con buen éxito para estimular la producción de glóbulos rojos, granulocitos y de monocitos en algunas patologías con daño a la médula ósea. Después de varios años de aplicación clínica, el uso de los interferones alfa, beta y gamma se han visto limitados a infecciones como la hepatitis B o C y algunos tipos de cáncer como la leucemia de células peludas y la leucemia granolocítica crónica. Las otras citocinas, como las interleucinas 2, 3, 4, 6 y el factor estimulante de colonias de monocitos, empiezan a mostrar su utilidad terapéutica en algunos ensayos clínicos. Se espera que en el futuro algunas de ellas, solas o combinadas con otras u otros activadores inmunológicos curen enfermedades como el síndrome de inmunodeficiencia adquirida o el cáncer

Cytokine regulation of expression of class I MHC antigens

No abstract available.

Cariótipo de paciente com leucemia mielóide crônica tratado com interferon / Karyotype of the chronic myeloid leukemia patient treated with interferon

Neste trabalho, estudamos citogeneticamente um paciente com LMC tratado com interferon. Foram analisadas 12 células metafásicas. O cromossomo Pb foi encontrado em 100 por cento das células analisadas e apenas uma apresentou isocromossomo 17q. Este achado, apesar de näo ser clonal, pode indicar prenúncio da fase blástica. Porém, o tratamento com interferon pode estar exercendo pressäo sobre as células i(17q), näo permitindo que proliferem bloqueando o início da fase blástica. Portanto acreditamos que o tratamento com interferon é capaz de sprimir as células com alteraçöes cromossômicas pós-philadelfia, melhorando o prognóstico do paciente

Tratamiento de la esclerosis múltiple con interferones / Treatment of multiple sclerosis with interferons

Despite the important achievements in clinical and experimental aspects of demylinating diseases and multiple sclerosis (MS), its pathogenesis still remains unknown. The most commonly held view is that it is an autoimmune disease, related in some way to a viral infection, that occurs in genetically susceptible hosts. Based on this, many current treatments for MS are designed to modulate the immune response and the interferons are an example. Only beta interferon has a dose dependent efficacy in phase III clinical trials, as treatment for remitting-relapsing forms. It produces a reduction in exacerbation rates and in the burden of the disease, measured by Magnetic Resonance imaging. The clinical use of beta interferon, considering the cost and large tretament period, must be cautious, reserving it only for confirmed remitting-relapsing modalities of MS. There is no clear cut evidence that beta interferon is useful for chronic-progressive MS

Uso del interferón en la papilomatosis laríngea / Use of interferon in the laryngeal papilomatosis

Existe gran controversia sobre la importancia del uso del interferón en la papilomatosis laríngea. Hay autores que son fervientes partidarios de su uso, en cambio otros tienen sus reservas sobre la eficacia en el control de la papilomatosis laríngea. Se hace una revisión de la literatura sobre el tema: tanto del origen viral de la papilomatosis laríngea y por consiguiente la justificación del uso del interferón, como también de la posición de los diferentes autores tanto defensores como detractores. Se concluye que el interferón en la papilomatosis laríngea se justificaría, solamente, en los casos de papilomatosis agresiva

Bases para el uso combinado de los interferones y de los retinoides en oncología clínica / Basis for the combined use of interferon and retinoid in clinical oncology

El acido retinoico y el interferón alfa tienen actividad limitada en el tratamiento de cáncer avanzado. La información obtenida de los cultivos celulares indican que, en combinación, estos agentes tienen incremento de la actividad biológica modulando el crecimiento y la diferenciación en un número de tipos celulares malignos. Trabajos clínicos recientes sobre el tratamiento de algunos carcinomas avanzados de células escamosas informan actividad terapéutica con este régimen. Este artículo revisa los datos preclínicos obtenidos al evaluar el ácido retinoico en combinación con interferones